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Biomedical subjects

Birgit Assmus

Publications and source records attributed to Birgit Assmus.

14 recordsLinked to original sources
PubMed2006

Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial.

AIMS: To investigate the clinical outcome after intracoronary administration of autologous progenitor cells in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: Using a double-blind, placebo-controlled multicentre trial design, we randomized 204 patients with successfully reperfused AMI to receive intracoronary infusion of bone-marrow-derived progenitor cells (BMCs) or placebo medium into the infarct artery 3-7 days after successful infarct reperfusion therapy. At 12 months, the pre-specified cumulative endpoint of death, myocardial infarction, or necessity for revascularization was significantly reduced in the BMC group compared with placebo (P=0.009). Likewise, the combined endpoint death, recurrence of myocardial infarction, and rehospitalization for heart failure was significantly (P=0.006) reduced in patients receiving intracoronary BMC administration. Intracoronary administration of BMC remained a significant predictor of a favourable clinical outcome by Cox regression analysis, adjusting for classical predictors of poor outcome after AMI. CONCLUSION: Intracoronary administration of BMCs is associated with a significant reduction of the occurrence of major adverse cardiovascular events after AMI. Large-scale studies are warranted to confirm the effects of BMC administration on mortality and morbidity in patients with AMIs.

Adolescent↗
PubMed2006

Intracoronary infusion of progenitor cells is not associated with aggravated restenosis development or atherosclerotic disease progression in patients with acute myocardial infarction.

AIMS: Experimental and clinical pilot studies suggest that intracoronary progenitor cell infusion can improve left ventricular function and remodelling after acute myocardial infarction (AMI). Since progenitor cells are also known to be involved in restenosis development and atherosclerosis progression, an increased restenosis rate may be a risk of intracoronary cell therapy. METHODS: We performed a retrospective study to compare quantitative angiographic measurements of the infarct target vessel in 83 patients with AMI treated with bare metal stent PCI (matched control) and in 83 patients receiving additional intracoronary progenitor cell infusion at a mean of 5 days post-AMI stent PCI and after 4 months. RESULTS: The late loss as a measure of neointima formation was similar between the control and the cell-treated group at follow-up (0.9+/-0.8 vs. 0.9+/-0.7 mm, P=0.9). Moreover, restenosis rate was comparable in both groups (35% control vs. 27% cell-treated group, P=0.2). Multivariable analysis excluded cell therapy as an independent significant predictor of increased late loss (P=0.4), whereas acute gain (P=0.012) and diabetes mellitus (P=0.002) were independent predictors of late loss. Finally, in the cell-treated group, target vessel revascularization rate remained at 28.9% during a median of >3 years of follow-up, thus excluding an effect on atherosclerotic disease progression. CONCLUSION: In patients with AMI successfully treated with bare metal stent PCI, additional intracoronary progenitor cell infusion does not lead to an increased neointima formation within the implanted stent within 4 months or aggravation of atherosclerotic disease progression.

Case-Control Studies↗
PubMed2006

Transcoronary transplantation of progenitor cells after myocardial infarction.

BACKGROUND: Pilot studies suggest that intracoronary transplantation of progenitor cells derived from bone marrow (BMC) or circulating blood (CPC) may improve left ventricular function after acute myocardial infarction. The effects of cell transplantation in patients with healed myocardial infarction are unknown. METHODS: After an initial pilot trial involving 17 patients, we randomly assigned, in a controlled crossover study, 75 patients with stable ischemic heart disease who had had a myocardial infarction at least 3 months previously to receive either no cell infusion (23 patients) or infusion of CPC (24 patients) or BMC (28 patients) into the patent coronary artery supplying the most dyskinetic left ventricular area. The patients in the control group were subsequently randomly assigned to receive CPC or BMC, and the patients who initially received BMC or CPC crossed over to receive CPC or BMC, respectively, at 3 months' follow-up. RESULTS: The absolute change in left ventricular ejection fraction was significantly greater among patients receiving BMC (+2.9 percentage points) than among those receiving CPC (-0.4 percentage point, P=0.003) or no infusion (-1.2 percentage points, P<0.001). The increase in global cardiac function was related to significantly enhanced regional contractility in the area targeted by intracoronary infusion of BMC. The crossover phase of the study revealed that intracoronary infusion of BMC was associated with a significant increase in global and regional left ventricular function, regardless of whether patients crossed over from control to BMC or from CPC to BMC. CONCLUSIONS: Intracoronary infusion of progenitor cells is safe and feasible in patients with healed myocardial infarction. Transplantation of BMC is associated with moderate but significant improvement in the left ventricular ejection fraction after 3 months.

Aged↗
PubMed2006

Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction.

BACKGROUND: Pilot trials suggest that the intracoronary administration of autologous progenitor cells may improve left ventricular function after acute myocardial infarction. METHODS: In a multicenter trial, we randomly assigned 204 patients with acute myocardial infarction to receive an intracoronary infusion of progenitor cells derived from bone marrow (BMC) or placebo medium into the infarct artery 3 to 7 days after successful reperfusion therapy. RESULTS: At 4 months, the absolute improvement in the global left ventricular ejection fraction (LVEF) was significantly greater in the BMC group than in the placebo group (mean [+/-SD] increase, 5.5+/-7.3% vs. 3.0+/-6.5%; P=0.01). Patients with a baseline LVEF at or below the median value of 48.9% derived the most benefit (absolute improvement in LVEF, 5.0%; 95% confidence interval, 2.0 to 8.1). At 1 year, intracoronary infusion of BMC was associated with a reduction in the prespecified combined clinical end point of death, recurrence of myocardial infarction, and any revascularization procedure (P=0.01). CONCLUSIONS: Intracoronary administration of BMC is associated with improved recovery of left ventricular contractile function in patients with acute myocardial infarction. Large-scale studies are warranted to examine the potential effects of progenitor-cell administration on morbidity and mortality.

Aged↗
PubMed2006

Effects of granulocyte colony simulating factor on functional activities of endothelial progenitor cells in patients with chronic ischemic heart disease.

OBJECTIVE: Bone marrow-derived circulating endothelial progenitor cells (EPCs) may contribute to regeneration of infarcted myocardium and enhance neovascularization. Granulocyte colony-stimulating factor (G-CSF) is well-established to mobilize hematopoietic stem cells (HSCs) and might, thereby, also increase the pool of endogenously circulating EPC. Therefore, we investigated the effects of G-CSF administration on mobilization and functional activities of blood-derived EPC in patients with chronic ischemic heart disease (CIHD). METHODS AND RESULTS: Sixteen patients with CIHD received 10 microg/kg per day subcutaneous G-CSF injection for 5 days. Leukocyte counts, the number of HSCs and EPCs, and the migratory response to VEGF and SDF-1 were analyzed before and after G-CSF-therapy. At day 5 of G-CSF treatment, the number of circulating leukocytes, CD34+ CD45+ and CD34+ CD133+ cells was significantly increased. Likewise, G-CSF treatment augmented the numbers of colony forming units with endothelial cell morphology (EC-CFU). However, the functional activity of the EPC as assessed by the migratory response to VEGF and SDF-1 was significantly reduced after G-CSF treatment (P<0.01). Because G-CSF was previously shown to cleave the CXCR4 receptor, we determined the surface expression of the 6H8 epitope of the CXCR4 receptor by fluorescence-activated cell sorter (FACS) analysis. Consistent with the reduced migratory capacity, the surface expression of the functionally active CXCR4 receptor was significantly reduced. To test the functional activity of the cultivated EPCs in vivo, cells were intravenously infused in nude mice after hind limb ischemia. EPCs, which were cultivated before G-CSF administration, increased blood flow recovery and prevented limb necrosis. However, infusion of EPCs, which were isolated 5 days after G-CSF treatment from the same patient, showed a reduced capacity to augment blood flow recovery and to prevent necrosis by 27%. CONCLUSIONS: G-CSF treatment effectively mobilizes HSCs and EPCs. However, the migratory response to SDF-1 and in vivo capacity of G-CSF-mobilized EPCs was significantly reduced.

Aged↗
PubMed2006

Facilitating coronary artery evaluation in MDCT using a 3D automatic vessel segmentation tool.

The purpose of this study was to investigate a 3D coronary artery segmentation algorithm using 16-row MDCT data sets. Fifty patients underwent cardiac CT (Sensation 16, Siemens) and coronary angiography. Automatic and manual detection of coronary artery stenosis was performed. A 3D coronary artery segmentation algorithm (Fraunhofer Institute for Computer Graphics, Darmstadt) was used for automatic evaluation. All significant stenoses (>50%) in vessels >1.5 mm in diameter were protocoled. Each detection tool was used by one reader who was blinded to the results of the other detection method and the results of coronary angiography. Sensitivity and specificity were determined for automatic and manual detection as well as was the time for both CT-based evaluation methods. The overall sensitivity and specificity of the automatic and manual approach were 93.1 vs. 95.83% and 86.1 vs. 81.9%. The time required for automatic evaluation was significantly shorter than with the manual approach, i.e., 246.04+/-43.17 s for the automatic approach and 526.88+/-45.71 s for the manual approach (P<0.0001). In 94% of the coronary artery branches, automatic detection required less time than the manual approach. Automatic coronary vessel evaluation is feasible. It reduces the time required for cardiac CT evaluation with similar sensitivity and specificity as well as facilitates the evaluation of MDCT coronary angiography in a standardized fashion.

Aged↗
PubMed2004

Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial.

OBJECTIVES: The Transplantation of Progenitor Cells And Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) trial investigates both safety, feasibility, and potential effects on parameters of myocardial function of intracoronary infusion of either circulating progenitor cells (CPC) or bone marrow-derived progenitor cells (BMC) in patients with acute myocardial infarction (AMI). BACKGROUND: In animal experiments, therapy with adult progenitor cells was shown to improve vascularization, left ventricular (LV) remodeling, and contractility after AMI. METHODS: A total of 59 patients with AMI were randomly assigned to receive either CPC (n = 30) or BMC (n = 29) into the infarct artery at 4.9 +/- 1.5 days after AMI. RESULTS: Intracoronary progenitor cell application did not incur any measurable ischemic myocardial damage, but one patient experienced distal embolization before cell therapy. During hospital follow-up, one patient in each cell group developed myocardial infarction; one of these patients died of cardiogenic shock. No further cardiovascular events, including ventricular arrhythmias or syncope, occurred during one-year follow-up. By quantitative LV angiography at four months, LV ejection fraction (EF) significantly increased (50 +/- 10% to 58 +/- 10%; p < 0.001), and end-systolic volumes significantly decreased (54 +/- 19 ml to 44 +/- 20 ml; p < 0.001), without differences between the two cell groups. Contrast-enhanced magnetic resonance imaging after one year revealed an increased EF (p < 0.001), reduced infarct size (p < 0.001), and absence of reactive hypertrophy, suggesting functional regeneration of the infarcted ventricles. CONCLUSIONS: Intracoronary infusion of progenitor cells (either BMC or CPC) is safe and feasible in patients after AMI successfully revascularized by stent implantation. Both the excellent safety profile and the observed favorable effects on LV remodeling, provide the rationale for larger randomized double-blind trials.

Adolescent↗
PubMed2004

Transplantation of progenitor cells after reperfused acute myocardial infarction: evaluation of perfusion and myocardial viability with FDG-PET and thallium SPECT.

Clinical outcome after myocardial infarction depends on the extent of irreversibly damaged myocardium. Implantation of bone marrow-/circulating blood-derived progenitor cells has been shown to improve contractile cardiac function after myocardial infarction in both experimental and initial clinical studies. In the present study, first observations of the effect of local intracoronary progenitor cell infusion on the regeneration of infarcted cardiac tissue after acute myocardial infarction was evaluated by means of 18F-fluorodeoxyglucose positron emission tomography (PET) and 201Tl single-photon emission computed tomography (SPECT). Twenty-six patients underwent intracoronary infusion of bone marrow-derived (BMCs) (15 patients) or circulating blood-derived endothelial progenitor cells (EPCs) (11 patients) 4+/-2 days after acute myocardial infarction. Based on a left ventricular segmentation model (17 segments), mean signal intensities as a parameter of viability and perfusion in the infarct zone and non-infarct areas were calculated quantitatively by PET and SPECT at baseline and at 4 months of follow-up. Transplantation of progenitor cells was associated with a significant increase in the mean signal intensity (MSI) in the infarct zone from 54.5% (25th and 75th percentiles: 47.7%, 60.0%) to 58.0% (52.7%, 66.7%) on PET (P=0.013) and from 58.0% (49.5%, 63.0%) to 61.5% (52.5%, 70.2%) on SPECT (P=0.005). Global left ventricular ejection fraction (LVEF) increased from 53.5% (42.6%, 60.0%) to 58.0% (53.0%, 65.8%) (P<0.001). In the five patients without an increase in MSI on PET, LVEF changed from 60.0% (50.0%, 64.0%) to 72.0% (64.0%, 75.5%) at follow-up. PET and SPECT did not show any significant changes in MSI in the non-infarct areas [from 73% (68.5%, 76.2%) to 73% (69.7%, 78.0%) for PET and from 72.0% (66.5%, 77.6%) to 73.0% (67.5%, 78.2%) for SPECT]. There were no significant differences in myocardial viability and perfusion between BMC and EPC infusion. These preliminary results show that coronary stenting and transplantation of progenitor cells result in a significant increase in myocardial viability and perfusion. Therapeutic effects can be reliably measured by PET and SPECT.

Female↗
PubMed2004

Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease.

BACKGROUND: Cell therapy with bone marrow-derived stem/progenitor cells is a novel option for improving neovascularization and cardiac function in ischemic heart disease. Circulating endothelial progenitor cells in patients with coronary heart disease are impaired with respect to number and functional activity. However, whether this impairment also extends to bone marrow-derived mononuclear cells (BM-MNCs) in patients with chronic ischemic cardiomyopathy (ICMP) is unclear. METHODS AND RESULTS: BM-MNCs were isolated from bone marrow aspirates in 18 patients with ICMP (ejection fraction, 38+/-11%) and 8 healthy control subjects (controls). The number of hematopoietic stem/progenitor cells (CD34+/CD133+), CD49d(+) (VLA-4) cells, and CXCR4+ cells did not differ between the 2 groups. However, the colony-forming capacity of BM-MNCs from patients with ICMP was significantly lower compared with BM-MNCs from healthy controls (37.3+/-25.0 versus 113.8+/-70.4 granulocyte-macrophage colony-forming units; P=0.009). Likewise, the migratory response to stromal cell-derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF) was significantly reduced in BM-MNCs derived from patients with ICMP compared with BM-MNCs from healthy controls (SDF-1, 46.3+/-26.2 versus 108.6+/-40.4 cells/microscopic field, P<0.001; VEGF, 34+/-24.2 versus 54.8+/-29.3 cells/microscopic field, P=0.027). To assess the in vivo relevance of these findings, we tested the functional activity of BM-MNCs to improve neovascularization in a hindlimb animal model using nude mice. Two weeks after ligation of the femoral artery and intravenous injection of 5x10(5) BM-MNCs, laser Doppler-derived relative limb blood flow in mice treated with BM-MNCs from patients with ICMP was significantly lower compared with mice treated with BM-MNCs from healthy controls (0.45+/-0.14 versus 0.68+/-0.15; P<0.001). The in vivo neovascularization capacity of BM-MNCs closely correlated with the in vitro assessment of SDF-1-induced migration (r=0.78; P<0.001) and colony-forming capacity (r=0.74; P<0.001). CONCLUSIONS: BM-MNCs isolated from patients with ICMP have a significantly reduced migratory and colony-forming activity in vitro and a reduced neovascularization capacity in vivo despite similar content of hematopoietic stem cells. This functional impairment of BM-MNCs from patients with ICMP may limit their therapeutic potential for clinical cell therapy.

Adolescent↗
PubMed2003

Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labeling.

BACKGROUND: Transplantation of endothelial progenitor cells (EPCs) improves vascularization and left ventricular function after experimental myocardial ischemia. However, tissue distribution of transplanted EPCs has not yet been monitored in living animals. Therefore, we tested whether radioactive labeling allows us to detect injected EPCs. METHODS AND RESULTS: Human EPCs were isolated from peripheral blood, characterized by expression of endothelial marker proteins, and radioactively labeled with [111In]indium oxine. EPCs (106) were injected in athymic nude rats 24 hours after myocardial infarction (n=8) or sham operation (n=8). Scintigraphic images were acquired after 1, 24, 48, and 96 hours after EPC injection. Animals were then killed, and specific radioactivity was measured in different tissues. At 24 to 96 hours after intravenous injection of EPCs, approximately 70% of the radioactivity was localized in the spleen and liver, with only approximately 1% of the radioactivity identified in the heart of sham-operated animals. After myocardial infarction, the heart-to-muscle radioactivity ratio increased significantly, from 1.02+/-0.19 in sham-operated animals to 2.03+/-0.37 after intravenous administration of EPCs. Injection of EPCs into the left ventricular cavity increased this ratio profoundly, from 2.69+/-1.54 in sham-operated animals to 4.70+/-1.55 (P<0.05) in rats with myocardial infarction. Immunostaining of cryosections from infarcted hearts confirmed that EPCs homed predominantly to the infarct border zone. CONCLUSIONS: Although only a small proportion of radiolabeled EPCs are detected in nonischemic myocardium, myocardial infarction increases homing of transplanted EPCs in vivo profoundly. Radiolabeling might eventually provide an useful tool for monitoring the fate of transplanted progenitor cells and for clinical cell therapy.

Animals↗
PubMed2003

HMG-CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes.

Endothelial progenitor cells (EPCs) play an important role in postnatal neovascularization of ischemic tissue. Ex vivo expansion of EPCs might be useful for potential clinical cell therapy of myocardial ischemia. However, cultivation of primary cells leads to cellular aging (senescence), thereby severely limiting the proliferative capacity. Therefore, we investigated whether statins might be able to prevent senescence of EPCs. EPCs were isolated from peripheral blood and characterized. After ex vivo cultivation, EPCs became senescent as determined by acidic beta-galactosidase staining. Atorvastatin or mevastatin dose-dependently inhibited the onset of EPC senescence in culture. Moreover, atorvastatin increased proliferation of EPCs as assessed by BrdU incorporation and colony-forming capacity. Whereas geranylgeranylpyrophosphate or farnesylpyrophosphate reduced the senescence inhibitory effect of atorvastatin, NO synthase inhibition, antioxidants, or Rho kinase inhibitors had no effect. To get further insights into the underlying downstream effects of statins, we measured telomerase activity and determined the expression of various cell cycle regulatory genes by using a microarray assay. Whereas telomerase activity did not change, atorvastatin modulated expression of cell cycle genes including upregulation of cyclins and downregulation of the cell cycle inhibitor p27Kip1. Taken together, statins inhibited senescence of EPCs independent of NO, reactive oxygen species, and Rho kinase, but dependent on geranylgeranylpyrophosphate. Atorvastatin-mediated prevention of EPC senescence appears to be mediated by the regulation of various cell cycle proteins. The inhibition of EPC senescence and induction of EPC proliferation by statins in vitro may importantly improve the functional activity of EPCs for potential cell therapy.

Atorvastatin↗
PubMed2002

Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI).

BACKGROUND: Experimental studies suggest that transplantation of blood-derived or bone marrow-derived progenitor cells beneficially affects postinfarction remodeling. The safety and feasibility of autologous progenitor cell transplantation in patients with ischemic heart disease is unknown. METHODS AND RESULTS: We randomly allocated 20 patients with reperfused acute myocardial infarction (AMI) to receive intracoronary infusion of either bone marrow-derived (n=9) or circulating blood-derived progenitor cells (n=11) into the infarct artery 4.3+/-1.5 days after AMI. Transplantation of progenitor cells was associated with a significant increase in global left ventricular ejection fraction from 51.6+/-9.6% to 60.1+/-8.6% (P=0.003), improved regional wall motion in the infarct zone (-1.5+/-0.2 to -0.5+/-0.7 SD/chord; P<0.001), and profoundly reduced end-systolic left ventricular volumes (56.1+/-20 mL to 42.2+/-15.1 mL; P=0.01) at 4-month follow-up. In contrast, in a nonrandomized matched reference group, left ventricular ejection fraction only slightly increased from 51+/-10% to 53.5+/-7.9%, and end-systolic volumes remained unchanged. Echocardiography revealed a profound enhancement of regional contractile function (wall motion score index 1.4+/-0.2 at baseline versus 1.19+/-0.2 at follow-up; P<0.001). At 4 months, coronary blood flow reserve was significantly (P<0.001) increased in the infarct artery. Quantitative F-18-fluorodeoxyglucose-positron emission tomography analysis revealed a significant (P<0.01) increase in myocardial viability in the infarct zone. There were no differences for any measured parameter between blood-derived or bone marrow-derived progenitor cells. No signs of an inflammatory response or malignant arrhythmias were observed. CONCLUSIONS: In patients with AMI, intracoronary infusion of autologous progenitor cells appears to be feasible and safe and may beneficially affect postinfarction remodeling processes.

Cells, Cultured↗
PubMed2002

Angiotensin II-induced upregulation of MAP kinase phosphatase-3 mRNA levels mediates endothelial cell apoptosis.

Angiotensin II (Ang II) is central to the pathobiology of atherosclerosis. In endothelial cells (EC), Ang II induces apoptosis. The MAP kinase ERK1/2 plays a key role in regulating cell survival. We therefore investigated the effect of Ang II on ERK1/2. Incubation of EC with Ang II led to the dephosphorylation of ERK1/2 (43% of control). To characterize the phosphatase involved, we investigated the effect of Ang II on MAP kinase phosphatase expression. Ang II induced MAP kinase phosphatase-3 (MKP-3) mRNA levels to about 2-fold, whereas MKP-1 expression was not affected. Transfection with a dominant negative MKP-3 construct (dnMKP-3mt) prevented the Ang II-induced ERK1/2 dephosphorylation and apoptosis in EC (p < 0.001). ERK1/2 inactivation has been shown to result in the dephosphorylation and proteasomal degradation of the antiapoptotic protein Bcl-2. Ang II induced the degradation of Bcl-2 wild type, whereas the dephosphorylation-resistant Bcl-2 construct mimicking phosphorylation by ERK1/2 was resistant to Ang II stimulation. These results indicate that Ang II-induced apoptosis signaling in human EC is mediated via MKP-3-dependent dephosphorylation of ERK1/2, which in turn leads to the degradation of Bcl-2.

Angiotensin II↗